Is Neuraxial Clonidine a Safer Alternative to Opioids for Chronic Pain? An Alternative Worth Exploring

Objective: Exploring the potential role of clonidine as an alternative to the currently available neuraxial medication options for the management of chronic pain. Methods: A comprehensive literature search was conducted investigating the treatment of chronic pain using clonidine over the past 73 years. A stepwise filtering approach was used to obtain articles addressing neuraxial treatment of chronic pain in adults. Selected articles were assessed for their levels of evidence followed by a discussion of their contribution to the understanding of the role of clonidine in chronic pain management. Results: Out of 1,035 articles that described the administration of clonidine for chronic pain management, seven articles met all of the inclusion criteria. Their levels of evidence ranged from 1a to 4 (Oxford Centre CEBM). Neuraxial administration of clonidine was found to be effective in the treatment of chronic pain, often exhibiting a synergistic effect with other analgesics to provide pain reduction with reduced opioid use. The most common side effect was hypotension, in some cases reported to have been serious. Conclusion: The use of neuraxial clonidine, in either a primary or adjunctive role, appears promising as an effective treatment for chronic pain. © 2020 Nagy Mekhail. Hosting by Science Repository. All rights reserved.


Introduction
Opioids continue to represent the medical basis in the treatment algorithm for intractable chronic pain. Yet, its common side effects play mischief with the ability to secure sustained pain relief [1]. As the prevalence of chronic pain in the United States continues to increase, advances in neuraxial medications seem necessary to expand the therapeutic algorithm for chronic pain conditions such as complex regional pain syndrome (CRPS), postherpetic neuralgia, diabetic neuropathy, cancer pain and chronic radiculopathy with or without previous back surgery [2][3][4].
Clonidine is an alpha-2 adrenoreceptor agonist that was initially developed as a nasal decongestant and an antihypertensive. It was subsequently found to be an effective adjuvant for the treatment of chronic neuropathic pain. When administered neuraxially, clonidine interferes with nociceptive impulses by activating the alpha-2 adrenoreceptors in the dorsal horn of the spinal cord and other sites. Early studies have demonstrated that intrathecal clonidine is effective in treating chronic pain, and epidural administration was found to have double the analgesic potency of intravenous administration, as well as allowing for medication dose reduction intra-and postoperatively [5][6][7]. Clonidine has been FDA approved in combination with opioids for the treatment of refractory cancer, shifting the opioid pain response curve to the left [8]. Obtaining the same sedation level at different time intervals of intra and postoperative analgesia and demonstrating no significant difference of reduction in heart rate and blood pressure [6]. Furthermore, achieving greater pain relief at lower doses than with either opioids or clonidine alone [8][9][10].
Clonidine is a promising option in the pain management paradigm with several major advantages over opioids including the lack of addiction risk. Clonidine is particularly valuable when used to treat chronic pain patients who are opioid-tolerant, opioid non-responsive, allergic to opioids or at risk for opioid addiction [8][9][10].

Mechanism of Action
Clonidine-induced analgesia is mediated by both alpha-2A (including cingulate alpha-2A) and alpha-2 non-A adrenoreceptors [11,12]. Activation of these receptors leads to decreased release of norepinephrine at both central and peripheral adrenergic terminals [13]. Norepinephrine is one of the important neurotransmitters that mediates the descending inhibitory pathway in nociception [14]. Animal studies have provided evidence of the anti-nociceptive effects of clonidine. Clonidine-mediated analgesia could be due to: 1) blockade of C fiber conduction; 2) inhibition of glutamate and substance P release or increase in nitric oxide (NO) or *Gamma Aminobutyric Acid (GABA) release 3) blockade of *N-methyl-D-aspartate (NMDA) receptors activation; 4) stimulation of depolarization-induced acetylcholine release in a neuropathic state and 5) inhibition of peripheral and central neuroinflammation [15][16][17][18][19][20][21][22].

I Research Question
"What is the published evidence for safety and effectiveness of intrathecal or epidural clonidine for the management of chronic pain?" These studies were reviewed with regard to clinical application, dosage and route of administration, efficacy and potential side effects and complications. iii.
Articles were limited to: English language, adult, and epidural/intrathecal as route of administration. iv.
The level of evidence for each article selected for inclusion was determined based on the concept outlined by the Oxford Centre for Evidence-Based Medicine (CEBM) ( Table 1). v.
Results were filtered using the stepwise approach as shown in the flowchart in (Figure 1). Case-series (and poor quality cohort and casecontrol studies § §) Case-series (and poor quality prognostic cohort studies***) Case-control study, poor or non-independent reference standard Case-series or superseded reference standards Analysis with no sensitivity analysis 5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" Expert opinion without explicit critical appraisal, or based on economic theory or "first principles"

Results
We obtained 42749 results after selecting the following keywords for clonidine: Clonidine derivative or clonidine displacing substance or clonidine or chlorthalidone plus clonidine/ or clonidine-induced catalepsy or clonidine.mp. 74244 from chronic pain.mp. or exp chronic pain. However, subsequently a combination of the two findings 1035 findings included both terms (clonidine and chronic pain). After adding limitations for epidural and intrathecal route of administration, as well as English language and age group, we collected 15 findings. Out of these, 7 articles were included, since the remaining focused on acute pain. Table 2 summarizes each of the studies meeting the inclusion criteria and the related level of evidence for each study according to Oxford CEBM (Table 1) [23]. Five studies were randomized, controlled trials (Level 1b), one was retrospective (Level 2b), and one was a case report (Level 4). Patient was pain-free for over two years using the same medication dosages.

I Level of Evidence 1b Studies
In a study by Rauck et al., 19 patients with CRPS with significant allodynia and hypersensitivity received intrathecal injections of clonidine (100 mcg) or adenosine (2 mg) in a randomized, double-blind, crossover study [24]. Each patient randomly received either a clonidine injection or an adenosine injection at the initial visit, then received an injection of the other medication at a second visit. Success was defined as a greater than 30% pain reduction on a visual analog pain score (VAS) scale within 2 hours of medication injection. Fifty-three percent (10/19) reported achieving the success criterion with clonidine, compared to 26% (5/19) with adenosine, a non-significant difference with P = 0.20. The pain scores for patients receiving clonidine improved significantly from pre-injection baseline to post-injection time, with significant reductions of both the area as well as the intensity of the hyperalgesia and allodynia; this effect was not seen in patients receiving adenosine. One limitation of this study was the use of a single clonidine dose level (100 mcg) instead of the evaluation of multiple dose levels. In an earlier study by the same author, 26 patients with CRPS received epidural injections of clonidine 300 mcg, 700 mcg, or saline, on subsequent days and in random order, while continuously evaluating pain with VAS [5]. Both doses of clonidine significantly reduced VAS by similar amounts within 20 minutes and pain relief lasted throughout the 6-hour monitoring period. Patients who initially responded to clonidine continued with an infusion for 43 days using a dose range of 14-50 mcg/h.
In a double-blind randomized crossover study evaluating the effects of clonidine alone or in combination with lidocaine in patients with chronic pain, clonidine was found to have a supra-additive analgesic effect.
Patients received an epidural injection of clonidine (150 mcg), lidocaine (40 mg), and a combination of clonidine (150 mcg) plus lidocaine (40 mg), with a median duration of pain relief of 2, 3, and 6 hours, respectively [10]. The majority of patients who completed the three treatment arms (12 of 17) reported pain relief with the combination therapy and none reported pain relief with lidocaine alone.
In a randomized, double-blind study of 85 cancer patients having either neuropathic or somatic/visceral cancer pain despite large doses of opioids or with therapy-limiting side effects from opioids, the treatment group received a continuous epidural infusion of clonidine at a rate of 30 mcg/h for 14 days, while the control group received an epidural saline infusion. Patients were randomized after a week of epidural morphine titration phase [25]. The treatment group reported a significant reduction in pain intensity and had a higher success rate (defined as 50% or greater pain relief) than the control group (45% vs. 21%). Epidural clonidine was found to be particularly effective in patients with neuropathic pain when analysed as a subgroup. The most common side effects in the treatment group were hypotension, sedation and dry mouth and the abrupt discontinuation of clonidine led to rebound hypertension in 4 subjects, one of whom suffered a cerebrovascular accident. It should be noted that the duration of the treatment was short (14 days), and the authors did not report a continuation of pain relief for longer terms. Another important aspect is that all patients received rescue epidural morphine.
A 15-patient randomized, double-blind study was performed to evaluate the effectiveness of intrathecally administered clonidine alone, morphine alone, or a combination of morphine and clonidine to treat severe debilitating neuropathic pain after spinal cord injury [26]. First day (saline, 0.2 -1.0 mg of morphine, or 50 -100 mcg of clonidine). If there was no pain relief or adverse side effects (sedation or effect on respiratory function), the subject received an increased dose of the same drug (1.5 times the initial dose) on the second day and two times the initial dose on day 3, with pain and vital signs being evaluated for 6 hours. There was nearly equal mean pain relief with either medication alone when compared to baseline (20% reduction from baseline with morphine and 17% with clonidine), and a 37% reduction with a combination of a half-dose each of morphine and clonidine. Neither medication alone resulted in greater pain reduction than saline placebo, although the mixture resulted in significant pain reduction (P = 0.0084), demonstrating a synergistic effect.

II Level of Evidence 2b Study
In a retrospective study evaluating the effectiveness of intrathecal clonidine, charts for 15 patients with CRPS, neuropathic pain and cancer pain were reviewed [27]. All patients received an initial trial of a single injection and/or a short-term infusion of clonidine, with ten patients reporting significant pain relief (>50% decrease in VAS score) and subsequently receiving a continuous long-term intrathecal infusion. Pain relief maintenance with clonidine alone varied widely from a few days until 11 months, with a daily dose of 75-950 mcg. Patients who failed clonidine alone, went on to receive a combination of intrathecally infused clonidine/opioid (Clonidine: 52-260 mcg/day; Hydromorphone: 1300-2600 mcg/day) and achieved pain relief that lasted 19-29 months.

III Level of Evidence 4 Study
In a case report of a patient with cervicobrachialgia receiving a combination of morphine (250 mcg) and clonidine (19 mcg) intrathecally daily for two years, the effect of morphine was potentiated by clonidine to achieve the desired analgesia with lower doses of morphine, demonstrating the opioid dose sparing effects of clonidine [28].

Discussion
Insufficient evidence supporting the effectiveness of opioids in the management of chronic neuropathic pain drives the need for drug alternatives [29]. The use of clonidine could avoid opioid-related complications including addiction, respiratory depression, pruritus, urinary retention, constipation, endocrine abnormalities and opioidinduced hyperalgesia. In addition, clonidine could be a potential alternative to steroids in epidural injections in vulnerable patient populations such as diabetic, hypertensive and osteoporotic [30,31].
The analgesic effects of clonidine have been recognized and applied for over 30 years, including oral and transdermal administration for postoperative and chronic pain [32,33]. Continuous epidural clonidine in doses of 25-50 mcg/h has been found to have beneficial effects in various study populations treated with spine instrumentation and orthopedic procedures. On the other hand, intrathecal clonidine has been administered in lesser doses of 15-40 mcg/h to avoid possible hypotension and sedation side effects with good quality evidence to support this use [34].

Efficacy
Clonidine treatment has been reported to be effective for complex regional pain syndrome (CRPS), failed back surgery syndrome (FBSS), visceral pain, cancer-related chronic pain and postherpetic neuralgia [35]. Epidural or intrathecal clonidine produces dose-dependent analgesia in patients with chronic pain. A mean reduction in pain of approximately 35% has been observed in clinical trials when using a 100-mcg dose [24]. Of interest, when opioids fail to provide significant pain relief in cases of neuropathic or mixed neuropathic-nociceptive cancer pain, additional epidural administration of clonidine has been shown to be effective in providing pain relief and may reduce the rate of opioid dose escalation [25,36,37]. This could be explained, in part, by the fact that alpha-2 adrenergic agonists potentiate the analgesic effects of opioids through synergism with delta receptors [28]. An important advantage of adding clonidine is reduction of the risk of opioid-induced side effects [38].
Most of the reported research into neuraxial administration of clonidine to treat chronic pain was performed over 20 years ago. Early studies utilized multiple or continuous infusion with far greater success. In a study of 26 patients with chronic reflex sympathetic dystrophy performed by Rauck et al., clonidine was infused over 7 to 225 days and provided significant pain relief [5]. Glynn and O'Sullivan found that while clonidine alone provided significant pain relief in nearly a quarter of the patients treated using three separate bolus injections, three times as many patients found the best relief with a combination of clonidine and lidocaine administered in the same fashion [10]. Other researchers also found evidence that clonidine may be more effective when combined with other agents than when used alone. Eisenach et al. compared the use of clonidine with a saline placebo in 85 patients with severe cancer pain, all of whom were also receiving patient-controlled on-demand morphine. The authors reported successful analgesia in twice as many patients who received clonidine as for those receiving saline placebo over 14 days [25]. In a study reported by Siddall et al., the combination of clonidine and morphine was found to be more effective in relieving chronic pain from spinal cord injuries in 15 patients than either medication alone [26]. Van Melkebeke et al. also reported the successful use of a combination of clonidine and morphine in their report on a single patient with chronic cervicobrachialgia, for which a lower dose of morphine was effective when augmented by the addition of clonidine [28].
More recently, intrathecal single bolus administration of clonidine was compared to adenosine in order to evaluate alternatives to opioids in 19 patients with CRPS. While nearly twice as many patients met the goal of >30% pain relief after receiving clonidine than adenosine, the difference was not statistically significant [24]. A significant portion of both groups did not attain the pain relief goal. The results of a study of 15 patients with either CRPS, neuropathic pain or cancer pain reported by Ackerman et al. also illustrate the benefit of combined medications over clonidine alone. While 10 patients reported initial pain relief with just clonidine, all 10 converted at some point to the addition of opioids to the intrathecal clonidine therapy to improve pain relief [27].

Side Effects and Complications
The reported side effects of clonidine include dose-dependent sedation or somnolence as well as hypotension, nausea, headache and dizziness [5,[24][25][26][27]. Eisenach et al. described six of 38 patients treated with clonidine (15.8%) as experiencing the serious adverse event of "dizziness/hypertension/hypotension" [25]. Rauck et al. reported that one of 20 patients (5.0%) complained of weakness in both legs following clonidine administration, although no distinct cause was found, and the weakness gradually resolved overnight [24]. It is important to note that hypotension occurs with oral and transdermal use and is consistent with clonidine's pharmacological effect. Supportive care for resulting hypotension with proper hydration is recommended. Rarely, vasopressor medications such as dopamine and norepinephrine have been used to treat severe hypotension. Other drugs including naloxone and atropine have been mentioned in the literature with inconsistent results [39]. A risk of rebound hypertension also exists following the sudden withdrawal of clonidine, such as might occur from a dislodged catheter. The potential resulting acute hypertensive crisis may require management using both alpha and beta-blockade [40,41].

Limitations
The scarcity of clinical trials assessing neuraxial clonidine as the sole medication for pain control was the main limitation of our study. Questions such as long-term pain relief as well as comparison of clonidine alone vs. placebo are still unanswered. We observed a substantial additive effect when used in combination with other medications, especially opioids. Since there is vast evidence of pharmacological effectiveness, as well as the additive analgesic properties of clonidine, we invite the chronic pain research community to consider this medication for non-superiority and other prospective trials.

Conclusion
As documented in publications spanning decades, albeit limited in number, neuraxial clonidine could be an asset medication included in the treatment algorithm for chronic neuropathic pain. The use of clonidine could decrease or even avoid significant side effects associated with opioids including addiction, respiratory depression, pruritus, urinary retention, constipation and opioid-induced hyperalgesia. Further large and well-controlled studies are needed to substantiate the therapeutic benefits of clonidine for treatment of pain and to standardize its proper dosage for different routes of administration.